The long range objective of this project is to understand fundamental mechanisms of ventilatory control, particularly mechanisms underlying the ventilatory response to physical activity. In this project period, we will continue to investigate neural mechanisms causing short and long term modulation of the ventilatory response to mild or moderate exercise. Short term modulation causes immediate (within trial) changes in the exercise ventilatory response whereas long term modulation changes systems responses over a time span of many trials. We also propose to begin investigations concerning the significance of short and long term modulation in compensating for impaired lung function during disease. Experiments will be conducted using awake goats trained to run on a treadmill as an experimental model. The specific aims are: 1) to test the hypothesis that short term modulation (STM) with increased respiratory dead space requires changes in spinal respiratory neuron excitability via descending serotonergic mechanisms. Goats with chronic subarachnoid catheters in the thoracic spinal cord will be used to determine the roles of 5-HT1 and 5-HT2 serotonin receptor subtypes, and to determine if STM can be pharmacologically enhanced via spinal serotonin reuptake inhibition. 2) to test the hypothesis that repeated CO/2-chemoreceptor stimulation during exercise augments ventilatory responses during future exercise trials (i.e., long term modulation, LTM) via serotonergic mechanisms. We propose to determine if pretreatment with a serotonergic neurotoxin (5,7-DHT) blocks LTM and if serotonin reuptake inhibition augments LTM. 3) to test the hypothesis that spinal serotonergic mechanisms are critical in maintaining an adequate exercise ventilatory response during models of lung disease. This objective will be met using two models of reversible lung disease: 1) partial disruption of the pulmonary circulation with a balloon catheter, thus creating an endogenous dead space; and 2) bronchoconstriction elicited by inhalation of methacholine. Short and long term modulation of the exercise ventilatory response indicate that the system adapts to changing conditions (e.g., pregnancy, onset of pulmonary disease, etc.). An understanding of these mechanisms may provide insight into normal compensatory processes, and the rationale for therapeutic intervention during disease. The results of these studies also have important implications in the design and interpretation of many studies on ventilatory control, since the central integration of respiratory inputs is commonly assumed be to be "hard wired."